Herpes Simplex Viruses infect the oral and genital mucosa and establishes a lifelong latent infection in the sensory ganglia. Ethanol exposure is known to increase both the risk and the severity of herpes infection. Since the majority of the population consumes ethanol on an acute or binge basis, it is important to understand the mechanism by which acute ethanol exposure suppresses the immune response to these viruses. The long-term objective of this application is to examine the role of ethanol plays in the immune response to HSV-1 and HSV-2. The central hypothesis is acute ethanol exposure influences the immune response to a mucosal virus infection by inhibiting proper activation of T cells and causing decreased virus clearance. Specific Aim one will examine how ethanol influences virus clearance from the mucosal epithelium by (1) looking at differences in virus clearance in mice expose to ethanol compared to vehicle, and (2) examining differences in the cytokine production and leukocyte infiltration at the site of infection. Since T cells are important for clearance of HSV-2 from the mucosa, Specific aim 2 will examine the effect of acute ethanol exposure on T cell effector function after virus infection. T cell function will be assessed by the ability to produce cytokines and lyse infected cells. Antigen-presenting cell function will also be examined to determine if ethanol inhibits T cell function through improper antigenic stimulation. Specific aim 3 will examine the effect of acute ethanol exposure on Toll-like receptor signaling and subsequent virus clearance by (1) determining differences in Toll-like receptor expression, (2) determining differences in virus clearance in Toll-like receptors knockout mice, and (3) determining if ethanol disrupts TLR signaling in antigen-presenting cells and in T cells leading to decreased virus clearance. Since over half the population consumes ethanol, it is important to understand how ethanol suppresses the immune response to viruses. The studies proposed in this application should provide insight into mechanisms by which ethanol increases the incidence of virus infections and may lead to development of immunotherapeutics to promote virus clearance. [unreadable] [unreadable] [unreadable]